Homology modeling of NR2B modulatory domain of NMDA receptor and analysis of ifenprodil binding
Homology modeling of NR2B modulatory domain of NMDA receptor and analysis of ifenprodil binding
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DOI：
10.1002/cmdc.200700091
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发表时间：
2007-10-01
期刊：
影响因子：
3.4
通讯作者：
Case, David A.
中科院分区：
文献类型：
--
作者：
Marinelli, Luciana;Cosconati, Sandro;Case, David A.
NMDA受体是谷氨酸门控离子通道（iGluR），参与几种重要的生理功能，如神经元发育、突触可塑性、学习和记忆。在iGluR中，可能最积极地研究了NMDA受体在慢性神经变性如阿尔茨海默病、帕金森病和亨廷顿病中的作用。最近的研究表明，NR 2B亚基的NTD通过与变构调节剂如原型化合物艾芬地尔的结合来调节离子通道门控。本文描述了NR 2B调节结构域的三维模型的构建，并首次进行了对接计算，在原子水平上定义艾芬地尔结合位姿，并充分解释所有可用的结构活性关系。此外，为了进一步了解艾芬地尔的作用机制，因为不完全清楚它是否结合并稳定在NR 2B调节结构域的开放或闭合构象上，这是NMDA拮抗剂的合理设计的基础，进行了MD模拟，然后进行了MM-PBSA分析。这些计算表明，RI-R2结构域的闭合构象，而不是开放的，构成了艾芬地尔的高亲和力结合位点，并且在艾芬地尔结合时发生闭合构象的深刻稳定。因此，对于一个合理的设计和/或虚拟筛选实验，RI-R2结构域的封闭构象应考虑和我们的三维模型可以提供有价值的提示NR 2B-选择性拮抗剂的设计。
NMDA receptors are glutamate-gated ion channels (iGluRs) that are involved in several important physiological functions such as neuronal development, synaptic plasticity, learning, and memory. Among iGluRs, NMDA receptors have been perhaps the most actively investigated for their role in chronic neurodegeneration such as Alzheimer's, Parkinson's, and Huntington's diseases. Recent studies have shown that the NTD of subunit NR2B modulates ion channel gating through the binding of allosteric modulators such as the prototypical compound ifenprodil In the present paper, the construction of a three-dimensional model for the NR2B modulatory domain is described and docking calculations allow, for the first time, definition of the ifenprodil binding pose at an atomic level and fully explain all the available structure activity relationships. Moreover, in an attempt to add further in-sight into the ifenprodil mechanism of action, as it is not completely clear if it binds and stabilizes on open or a closed conformation of the NR2B modulatory domain, a matter, which is fundamental for the rational design of NMDA antagonists, MD simulations followed by an MM-PBSA analysis were performed. These calculations reveal that the closed conformation of the RI-R2 domain, rather than the open, constitutes the high affinity binding site for ifenprodil and that a profound stabilization of the closed conformation upon ifenprodil binding occurs. Thus, for a rational design and/or for virtual screening experiments, the closed conformation of the RI-R2 domain should be taken into account and our 3D model can provide valuable hints for the design of NR2B-selective antagonists.